Gonococcal Porin IB Activates NF-κB in Human Urethral Epithelium and Increases the Expression of Host Antiapoptotic Factors

Binnicker, Matthew J.; Williams, Richard D.; Apicella, Michael A.

doi:10.1128/iai.72.11.6408-6417.2004

Cited by 42 publications

(44 citation statements)

References 47 publications

(50 reference statements)

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“…We suggest that the VK2/ E6E7-specific dys-regulation of p53 is a potential mechanism that may be utilized by gonococci to keep the host cell alive despite DNA damage. This observation is consistent with the anti-apoptotic features of N. gonorrhoeae (Binnicker et al, 2004;Howie et al, 2008).…”

Section: Discussionsupporting

confidence: 79%

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Vielfort

Söderholm

Weyler

et al. 2013

Journal of Cell Science

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SummaryThe constant shedding and renewal of epithelial cells maintain the protection of epithelial barriers. Interference with the processes of host cell-cycle regulation and barrier integrity permits the bacterial pathogen Neisseria gonorrhoeae to effectively colonize and invade epithelial cells. Here, we show that a gonococcal infection causes DNA damage in human non-tumor vaginal VK2/E6E7 cells with an increase of 700 DNA strand breaks per cell per hour as detected by an alkaline DNA unwinding assay. Infected cells exhibited elevated levels of DNA double-strand breaks, as indicated by a more than 50% increase in cells expressing DNA damage-response protein 53BP1-positive foci that co-localized with phosphorylated histone H2AX (cH2AX). Furthermore, infected cells abolished their expression of the tumor protein p53 and induced an increase in the expression of cyclin-dependent kinase inhibitors p21 and p27 to 2.6-fold and 4.2-fold of controls, respectively. As shown by live-cell microscopy, flow cytometry assays, and BrdU incorporation assays, gonococcal infection slowed the host cell-cycle progression mainly by impairing progression through the G2 phase. Our findings show new cellular players that are involved in the control of the human cell cycle during gonococcal infection and the potential of bacteria to cause cellular abnormalities.

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Section: Discussionsupporting

confidence: 79%

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Vielfort

Söderholm

Weyler

et al. 2013

Journal of Cell Science

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“…Diverse Bcl-2 family proteins have been found to play roles in the proapoptotic (39,40) and antiapoptotic (5,6,27,36) phenotypes observed upon N. gonorrhoeae infection in epithelial cells, but the extent to which individual Bcl-2 proteins act to mediate PMN survival has not been determined. A major regulator of neutrophil survival is thought to be the antiapoptotic Mcl-1 protein (1), whose role in inhibiting apoptosis in N. gonorrhoeae-infected PMNs remains to be examined.…”

Section: Discussionmentioning

confidence: 99%

Neisseria gonorrhoeae-Mediated Inhibition of Apoptotic Signalling in Polymorphonuclear Leukocytes

Chen

Seifert

2011

Infect Immun

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The human pathogen Neisseria gonorrhoeae recruits and interacts extensively with polymorphonuclear leukocytes (PMNs) during infection. N. gonorrhoeae is able to survive the bactericidal activity of these innate immune cells and can actively modulate PMN functions in vitro. PMNs are short-lived cells which readily undergo apoptosis, and thus the effect of N. gonorrhoeae infection on PMN survival has implications for whether PMNs might serve as an important site of bacterial replication during infection. We developed and validated an HL-60 myeloid leukemia cell culture model for PMN infection and used both these cells and primary PMNs to show that N. gonorrhoeae infection alone does not induce apoptosis and furthermore that N. gonorrhoeae can inhibit both spontaneous apoptosis and apoptosis induced by the intrinsic and extrinsic apoptosis inducers staurosporine (STS) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), respectively. N. gonorrhoeae infection also results in the activation of NF-B signaling in neutrophils and induces secretion of an identical profile of proinflammatory cytokines and chemokines in both HL-60 cells and primary PMNs. Our data show that the HL-60 cell line can be used to effectively model N. gonorrhoeae-PMN interactions and that N. gonorrhoeae actively inhibits apoptosis induced by multiple stimuli to prolong PMN survival and potentially facilitate bacterial survival, replication, and transmission.

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“…Our studies have shown that human primary genital tract epithelial cells can serve as surfaces for gonococcal biofilm formation with minimal, if any, effect on cell viability. This may reflect the ability of the gonococcus to induce antiapoptotic factors in these cells (2,3).…”

Section: Discussionmentioning

confidence: 99%

Biofilm Formation by Neisseria gonorrhoeae

et al. 2005

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Studies were performed in continuous-flow chambers to determine whether Neisseria gonorrhoeae could form a biofilm. Under these growth conditions, N. gonorrhoeae formed a biofilm with or without the addition of 10 M sodium nitrite to the perfusion medium. Microscopic analysis of a 4-day growth of N. gonorrhoeae strain 1291 revealed evidence of a biofilm with organisms embedded in matrix, which was interlaced with water channels. N. gonorrhoeae strains MS11 and FA1090 were found to also form biofilms under the same growth conditions. Cryofield emission scanning electron microscopy and transmission electron microscopy confirmed that organisms were embedded in a continuous matrix with membranous structures spanning the biofilm. These studies also demonstrated that N. gonorrhoeae has the capability to form a matrix in the presence and absence of CMP-N-acetylneuraminic acid (CMP-Neu5Ac). Studies with monoclonal antibody 6B4 and the lectins soy bean agglutinin and Maackia amurensis indicated that the predominate terminal sugars in the biofilm matrix formed a lactosamine when the biofilm was grown in the absence of CMP-Neu5Ac and sialyllactosamine in the presence of CMP-Neu5Ac. N. gonorrhoeae strain 1291 formed a biofilm on primary urethral epithelial cells and cervical cells in culture without loss of viability of the epithelial cell layer. Our studies demonstrated that N. gonorrhoeae can form biofilms in continuous-flow chambers and on living cells. Studies of these biofilms may have implications for understanding asymptomatic gonococcal infection.Neisseria gonorrhoeae is a human-adapted, gram-negative diplococcus that infects the human male and female reproductive tracts. N. gonorrhoeae infections in women frequently go unnoticed. This can eventually lead to serious upper genital tract infections which ultimately can lead to infertility (13). Currently, no studies have discussed the ability of N. gonorrhoeae to produce biofilms. Bacterial biofilms have been defined as communities of bacteria intimately associated with each other and included within an exopolymer matrix. These biological units exhibit their own properties, which are quite different from those shown by the single species in planktonic form (15). Numerous bacterial species are capable of producing biofilms. Biofilms confer a number of survival advantages to the bacteria, including increased resistance to antimicrobial agents (7,18).Our interest in the capability of N. gonorrhoeae to form a biofilm came about by observations made in our laboratory during 4-and 8-day infections of primary human urethral and cervical epithelial cells (8,12). Those studies showed that the gonococcus was forming microcolonies on these surfaces, and eventually these transitioned into structures that resembled bacterial biofilms.The purpose of this study was twofold. The first objective was to verify that N. gonorrhoeae can produce a biofilm both in biofilm chambers and over primary human genital tract epithelial cells in culture. The second objective was to gain information ...

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Gonococcal Porin IB Activates NF-κB in Human Urethral Epithelium and Increases the Expression of Host Antiapoptotic Factors

Cited by 42 publications

References 47 publications

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Neisseria gonorrhoeae-Mediated Inhibition of Apoptotic Signalling in Polymorphonuclear Leukocytes

Biofilm Formation by Neisseria gonorrhoeae

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